Discovery, synthesis and biological evaluation of dunnianol-based Mannich bases against methicillin-resistant Staphylococcus aureus (MRSA)

Dunnianol, a natural sesqui-neoligan derived from the leaves and stems of Illicium simonsii Maxim., has been found to possess moderate antibacterial activity. To improve the antibacterial activity and solubility of dunnianol, a series of dunnianol-based Mannich bases were prepared, and evaluated for their antibacterial activities. The most promising compound 5a' exhibited excellent antibacterial activity against Staphylococcus aureus and clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 1-2 µg/mL. Structure-activity relationships indicated that introduction of (dimethylamino)methyl at the ortho-position of phenolic hydroxyl group of dunnianol could obtain a more active compound. Mechanism study revealed that 5a' killed MRSA more rapid than vancomycin by disrupting the cell membrane. Moreover, 5a' was not susceptible to drug resistance development, and also showed low toxicity and good antibacterial efficacy in vivo. These results indicate that the dunnianol-based Mannich base 5a' could be a promising antibiotic candidate for further research.